Impact of non-invasive oxygen reserve index versus standard SpO2 monitoring on peripheral oxygen saturation during endotracheal intubation in the intensive care unit: Protocol for the randomized controlled trial NESOI2

In critically ill patients, endotracheal intubation (ETI) is lifesaving but carries a high risk of adverse events, notably hypoxemia. Preoxygenation is performed before introducing the tube to increase the safe apnea time. Oxygenation is monitored by pulse oximeter measurement of peripheral oxygen saturation (SpO2). However, SpO2 is unreliable at the high oxygenation levels produced by preoxygenation and, in the event of desaturation, may not decrease sufficiently early to allow preventive measures. The oxygen reserve index (ORI) is a dimensionless parameter that can also be measured continuously by a fingertip monitor and reflects oxygenation in the moderate hyperoxia range. The ORI ranges from 0 to 1 when arterial oxygen saturation (PaO2) varies between 100 to 200 mmHg, as occurs during preoxygenation. No trial has assessed the potential effects of ORI monitoring to guide preoxygenation for ETI in unstable patients. We designed a multicenter, two-arm, parallel-group, randomized, superiority, open trial in 950 critically ill adults requiring ETI. The intervention consists in monitoring ORI values and using an ORI target for preoxygenation of at least 0.6 for at least 1 minute. In the control group, preoxygenation is guided by SpO2 values recorded by a standard pulse oximeter, according to the standard of care, the goal being to obtain 100% SpO2 during preoxygenation, which lasts at least 3 minutes. The standard-of-care ETI technique is used in both arms. Baseline parameters, rapid-sequence induction medications, ETI devices, and physiological data are recorded. The primary outcome is the lowest SpO2 value from laryngoscopy to 2 minutes after successful ETI. Secondary outcomes include cognitive function on day 28. Assuming a 10% standard deviation for the lowest SpO2 value in the control group, no missing data, and crossover of 5% of patients, with the bilateral alpha risk set at 0.05, including 950 patients will provide 85% power for detecting a 2% between-group absolute difference in the lowest SpO2 value. Should ORI monitoring with a target of ≥0.6 be found to increase the lowest SpO2 value during ETI, then this trial may change current practice regarding preoxygenation for ETI. Trial registration: Registered on ClinicalTrials.gov (NCT05867875) on April 27, 2023.

Preoxygenation is universally recommended to reduce the risk of hypoxemia by increasing the apneic time without desaturation [7,8].However, the efficacy of preoxygenation is challenging to assess.Invasive PaO 2 measurement is the reference standard but cannot be performed continuously in real time at the bedside [9].Pulse oximetry estimation of peripheral oxygen saturation (SpO 2 ) is the oxygenation-monitoring tool most widely used during ETI in the ICU but detects hypoxemia only with a delay.Predicting hypoxemia during ETI is essential to allow timely preventive action [5].Importantly, SpO 2 does not reliably reflect PaO 2 in the moderate hyperoxia range achieved during preoxygenation.An end-tidal oxygen fraction (EtO 2 ) greater than 90% has been suggested as a preoxygenation target [10].However, EtO 2 cannot be monitored in most ICUs and may be biased by leaks around the mask [9].Moreover, in critically ill patients, notably those with acute hypoxemic respiratory failure, EtO 2 does not reflect oxygen reserves and therefore the effectiveness of preoxygenation [9,11].EtO 2 and SpO 2 may be high despite low PaO 2 values.Finally, during acute respiratory failure, the relevant data from this study will be made available upon study completion.
Funding: The NESOI2 trial is funded by the 2021 Programme Hospitalier de Recherche Clinique National of the French Ministry of Health (grant number PHRC-21-0202).The funder had no role in designing the trial and will have no role in collecting, analyzing, or interpreting the data; writing the trial report; or deciding to submit the trial report for publication.The funder had no role in writing the present manuscript or in deciding to submit it for publication.functional reserve capacity decreases and intrapulmonary shunting bypasses alveolar-capillary exchanges, so that EtO 2 does not reflect changes in PaO 2 [12].
Preoxygenation is usually performed for 3 to 4 minutes, but whether this duration is optimal in all patients remains unclear.In one study, increasing the duration of preoxygenation did not seem to improve efficacy [13].An additional parameter for optimizing the efficacy of preoxygenation and predicting hypoxemia during ETI would thus be welcome.
The oxygen reserve index (ORI) is a recently introduced parameter that can be continuously monitored using the Masimo Rad-97 finger monitor, which also monitors SpO 2 (Masimo, Irvine, CA).This dimensionless index reflects oxygenation levels in the moderate hyperoxia range targeted by preoxygenation, defined as PaO 2 between 100 and 200 mmHg.The ORI can range from 0.00 (PaO 2 = 100 mmHg) to 1.00 (PaO 2 = 200 mmHg).As indicated above, SpO 2 does not reflect oxygenation within this range, since values �97% may indicate PaO 2 levels between 90 and 600 mmHg [14].In contrast, a preoxygenation ORI target corresponding to the desired level of hyperoxia can be defined.In addition, ORI monitoring may provide an early warning that desaturation is about to occur.The potential usefulness of the ORI for this purpose has only been evaluated in small observational studies of patients undergoing scheduled surgery.ORI values dropped below 0.4 a median of 30  seconds before the onset of desaturation [15,16].Our recent observational NESOI study showed that, in nonhypoxemic patients undergoing ETI, ORI fell below 0.4 a median of 81  seconds before SpO 2 decreased below 97% during the apnea following induction [17].This time interval is sufficient to implement preventive measures such as mask ventilation or insertion of a supraglottic device.Interestingly, a high ORI value during preoxygenation independently predicted the absence of hypoxemia during ETI.
To assess the potential benefits of ORI monitoring during preoxygenation for ETI vs. the standard of care, we designed a multicenter randomized controlled trial in critically ill patients admitted to the ICU.The primary outcome is the lowest SpO 2 value recorded during ETI.

Material and methods
This manuscript was written in accordance with Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines [18].
The first patient was recruited on August 1, 2023.On January 11, 2024, 203 patients had been included, i.e., 21.3% of the planned sample.

Design, objectives, and setting
This protocol is for a multicenter, parallel-group, two-arm, randomized, controlled, trial comparing preoxygenation with a target ORI �0.6 for 1 minute to standard pulse-oximeter SpO 2 monitoring in critically ill patients undergoing ETI.The ORI is monitored using the Masimo Rad-97 monitor (Masimo, Irvine, CA, USA), which also measures SpO 2 .
The primary objective is to determine whether ORI monitoring during ETI with the abovedescribed target (designated "ORI monitoring" hereafter) increases the lowest SpO 2 value recorded by the Rad-97 monitor between the first introduction of the laryngoscope into the mouth and the end of the second minute following successful intubation.The secondary objectives are to determine whether ORI monitoring increases the lowest SpO 2 value that is recorded by the standard pulse oximeter (sensitivity analysis of the primary outcome) and/or that is observed in the predefined sub-groups detailed below (subgroup analysis of the primary outcome), to assess the safety of ORI monitoring based on the occurrence of immediately lifethreatening adverse events as described below, and to assess the efficacy of ORI monitoring based on the efficacy outcomes listed below.

Outcomes
The primary outcome is the lowest SpO 2 value measured by the Rad-97 monitor between the first introduction of the laryngoscope into the mouth and the end of the second minute following successful intubation.One of the secondary outcomes is the lowest SpO 2 value recorded by the standard pulse oximeter between the first introduction of the laryngoscope into the mouth and the end of the second minute following successful intubation; analysis of this outcome constitutes a sensitivity analysis of the primary outcome.
Additional secondary outcomes are the lowest SpO 2 values in subgroups defined based on body mass index (BMI) <30 vs. �30 kg/m 2 , hypoxemia vs. other reason for ETI, presence vs. absence of shock at inclusion, difficult vs. non-difficult ETI, and highest ORI during preoxygenation <0.6 vs. or �0.6.The immediately life-threatening adverse events considered for assessing the safety of ORI monitoring are severe hypoxemia defined as SpO 2 <80%, severe hypotension defined as systolic blood pressure (SBP) <90 mmHg, cardiac arrest, and death.Finally, the efficacy outcomes are ICU mortality, day-28 mortality, ICU and hospital stay lengths, and cognitive status on day 28 as evaluated using the validated French version of the modified Telephone Interview for Cognitive Status (F-TICS-m) [19].

Patients
The patients are being recruited at 20 French ICUs.Recruitment started on August 1, 2023 and is expected to end in December 2025.Consecutive adults requiring ETI in the ICU are eligible if not included in another study of ETI with an oxygen-based outcome criterion.Followup data are collected from trial inclusion to day 28 or death, whichever occurs first.The SPIRIT figure "Schedule of enrolment, interventions, and assessment for patients" is Fig 1.
Inclusion criteria.The inclusion criteria are ICU admission and a need for ETI and oxygen therapy (regardless of the device and flow rate) to obtain SpO 2 >97%.
Non-inclusion criteria.The non-inclusion criteria are age younger than 18 years, need for fiberoptic intubation (as determined by the attending intensivist), contraindication to laryngoscopy (e.g., unstable spinal-cord injury), insufficient time to include and randomize the patient (e.g., due to cardiac arrest), pregnancy, breastfeeding, being a correctional facility inmate, being under guardianship, not being covered by the French statutory health insurance system, and refusal of the patient (if competent) or next of kin to participate in the trial.

Randomization
Blocked randomization in a 1:1 ratio is achieved using a computer-generated random sequence of numbers, via the secure Ennov Clinical website (https://nantes-lrsy.ennov.com/EnnovClinical).At each center, the investigators will use their identification number and password to log into the site to enroll patients.The investigators will not be aware of the blocking details.Randomization is stratified based on center, intubating intensivist experience with ETI (expert vs. non-expert as defined below), and preoxygenation device used (NIV vs. other) (Fig 2).
The Rad-97 monitor is used in both groups but the display is masked and invisible to the intubating intensivist in the control group.Blinding of the intubating physician to trial group allocation is not feasible as the Rad-97 monitor itself is visible in both groups.However, Rad-97 ORI and SpO 2 values are recorded for the trial by a clinical research nurse not involved in the ETI procedure or in any other components of patient management.

Intervention and control arms
Intervention arm.The trial intervention consists in monitoring the ORI to achieve a value �0.6 for 1 minute during preoxygenation.The end of preoxygenation is defined as the start of induction, which occurs when the preoxygenation duration is at least 3 minutes and the ORI has been �0.6 for at least 1 minute.Thus, if ORI is �0.6 after 90 seconds of preoxygenation, induction is started 90 seconds later, after 3 minutes of preoxygenation.If ORI is �0.6 after 2.5 minutes of preoxygenation, induction is started 1 minute later, after 3.5 minutes of preoxygenation.In patients whose ORI remains <0.6 after 3 minutes of preoxygenation, the preoxygenation device is changed and preoxygenation continued until ORI is �0.6 for at least 1 minute.When this goal is not achieved, no maximal preoxygenation duration is specified given the pragmatic trial design; however, the investigators have been informed than 6 to 8 minutes of preoxygenation are expected to maximize benefits) (Fig 3).The ORI threshold of 0.6, corresponding to an estimated PaO 2 value of 160 mmHg, was chosen based on Control arm.In the control group, oxygenation is monitored according to the standard of care, that is, using the standard pulse oximeter available in each ICU (Fig 4A and 4B).The intubating intensivist will not be aware of the SpO 2 and ORI values provided by the Rad-97 monitor throughout the ETI procedure, which are recorded by the clinical research nurse.The Rad-97 monitor is masked and its alarms turned off.Preoxygenation lasts at least 3 minutes, with no maximum duration.
(A) Control arm.(B) Intervention arm.Standard of care applied in both arms.The other components of the standard of care are applied in both arms.Two intensivists are present throughout the entire ETI procedure, including at least one ETI expert defined as having at least 5 years of ICU experience or at least 1 year of ICU experience plus at least 2 years of operating-room experience [20].At least one of the two intensivists is trained in ORI monitoring.One of the two intensivists is the physician in charge of the patient.Preoxygenation is not started until the standard pulse oximeter and Rad-97 monitor are in place, on different fingers (ideally the forefinger for the standard pulse oximeter and the middle finger for the Rad-97 monitor) of the hand on the side contralateral to the arm equipped with the non-invasive blood-pressure cuff.
Selection of the preoxygenation device is at the discretion of the intubating intensivist.The options are a bag-valve mask with a flow rate of 60 L/min [21][22][23], non-rebreather mask with a flow rate of 60 L/min [23,24], NIV with 100% fraction of inspired oxygen (FiO 2 ) [25], and high-flow nasal cannula oxygen with 100% FiO 2 and a flow rate of 60 L/min [26,27].However, the protocol recommends NIV in patients with hypoxemia defined as a need for >8 L/min of supplemental oxygen to maintain SpO 2 �95%.Additional apneic oxygenation or/and apneic ventilation are allowed [28].The choice of induction drugs and their dosages is at the discretion of the intubating intensivist.However, the intubating intensivists are encouraged to follow international [7] and French [8] recommendations that etomidate (0.2-0.3 mg/kg) and ketamine (1-2 mg/kg) be Selection of the intubation device (laryngoscope or videolaryngoscope) and of blade type and size is at the discretion of the intubating intensivist.If the first attempt fails, the intubating intensivist is free to choose between repeating the same technique or switching to a different technique.The choice of this alternative technique is at the discretion of the intubating intensivist, who follows recommendations [7,8].Each insertion of the laryngoscope into the mouth is counted as an intubation attempt.Correct tube position is confirmed based on examination of four consecutive capnography cycles.Immediately after successful ETI, the balloon is inflated and the tube connected to the ventilator.

Data collection
At each participating ICU and for each patient, the trial data are entered into an electronic case report form (Ennov, Paris, France), in real time, by a clinical nurse not involved in patient management.The collected baseline data include demographics, medical history, reason for ICU admission, reason for ETI, BMI, skin color scale score (Fitzpatrick score [29]), criteria predicting difficult ETI and difficult mask ventilation [30], MACOCHA score [30], Knaus chronic disease score [31], and Charlson Comorbidity Index [32].The Sequential Organ Failure Assessment (SOFA) score [33] and Simplified Acute Physiology Score version II (SAPS II) [34] are recorded at ICU admission.The following are collected at inclusion and throughout the ETI procedure: hemodynamic data (SBP, diastolic blood pressure [DBP], mean arterial pressure [MAP], heart rate, and need for vasopressor therapy) and respiratory data (SpO 2 , ORI, respiratory rate, expiratory EtCO 2 , FiO 2 , positive end-expiratory pressure, and tidal volume).The data collection timepoints during ETI are inclusion, start of preoxygenation, end of preoxygenation (which coincides with start of induction, i.e., of hypnotic administration), start of laryngoscopy defined as the first introduction of the laryngoscope into the mouth, confirmation of successful intubation by capnography, and end of the second minute after successful intubation.ETI duration runs from induction initiation to confirmation of successful intubation (Fig 5).SpO 2 values are recorded from both the standard pulse oximeter and the Rad-97 monitor.The lowest SpO 2 values recorded by each device during the ETI procedure, the highest ORI value during preoxygenation, and the lowest SBP value during the ETI procedure are collected.Other routinely collected data are the preoxygenation device used; oxygenation device used between induction initiation and beginning of laryngoscopy, if any; duration of preoxygenation; drugs and doses used; intubation device used; need to perform a Sellick maneuver and/or re-ventilation (via a face mask or supraglottic device); Cormack-Lehane grade [35], POGO [36], and VIDIAC scores [37]; number of attempts before successful intubation (each attempt being defined as laryngoscope insertion into the mouth), with details; and adverse events during ETI.
Each patient is followed up until death or day 28, whichever occurs first.The following are recorded: SOFA score every day from day 1 to day 7, vital status at ICU discharge and on day 28, ICU and hospital stay lengths, and cognitive status on day 28 assessed during a telephone interview using the F-TICS-m [19].

Interim analysis
No interim analysis is planned.

Ethics and dissemination
Ethics.The NESOI-2 protocol was approved by the appropriate ethics committee (Comité de Protection des Personnes Ouest III) on March 20, 2023 (#2023-A00114-41) and was registered on ClinicalTrials.govon April 27, 2023 (#NCT05867875).Before trial inclusion, the patient, or next of kin if the patient is incompetent, is given an information document.Written or oral consent is then sought.If the patient is incompetent and no next of kin is available, trial inclusion is performed according to the emergency procedure set forth by French law, and informed consent is then sought as soon as a relative is available then when the patient recovers competency.
Dissemination.The policy for publishing the trial findings will comply with international recommendations [38] and the CONSORT statement (http://www.consort-statement.org).The findings will be published in peer-reviewed journals and presented during national and international scientific meetings.Communications and scientific reports relevant to the trial will be under the responsibility of the study coordinator (JBL), who will first obtain the approval of the other investigators.Guidelines for authorship issued by the International Committee of Medical Journal Editors will be followed.

Patient and public involvement
Neither the patients nor the public were involved in designing this protocol.They will not be involved in disseminating the findings.

Statistics
Sample size.Assuming a standard deviation of 10% for the lowest SpO 2 value in the control group [1], no missing data, and crossover of 5% of patients, with the bilateral alpha risk set at 0.05, the inclusion of 950 patients provides 85% power for detecting a 2% absolute betweengroup difference in the lowest SpO 2 value.
The recruitment rate predicted based on data from each participating center was 5 patients per month.The observed recruitment rate from trial initiation on August 1, 2023, to January 11, 2024, is consistent with this prediction.
Statistical analyses.The baseline characteristics of the overall population and each randomization group will be described as absolute number (%) for categorical variables and as mean±SD, range, and interquartile range for quantitative variables.No statistical tests will be performed to compare the two groups at baseline.
The main analysis will be based on the modified intention-to-treat population defined as all randomized patients who meet the legal criteria.Patients with SpO 2 values below 98% at the end of preoxygenation will be included in the modified intention-to-treat population.An analysis will also be performed in the per-protocol population obtained by excluding patients with ORI recording failure or ORI<0.6 at the end of preoxygenation.
The primary outcome will be compared between groups using a mixed-effects linear regression model to account for the stratification variables (center as a random effect and operator experience and preoxygenation device as fixed effects).In the event of non-normality of the residuals observed graphically (Q-Q plot), the usual transformations of the variables will be tested to improve the fit.The analyses of the effect of ORI monitoring on the primary outcome will be repeated in sub-groups defined by BMI (< or �30 kg/m 2 ), reason for ETI (hypoxemia vs. other), presence vs. absence of shock at inclusion, difficult vs. non-difficult ETI, and ORI<0.6 vs. �0.6.For each subgroup analysis, the statistical model described for the main analysis will be used, with incorporation of the interaction terms (subgroup variable by randomization group).The same statistical model will also be used to compare the groups regarding the lowest SpO 2 value recorded by the standard pulse oximeter.
The proportions of patients with at least one serious adverse event threatening short-term survival will be compared using a mixed-effects linear regression model.ICU and day-28 mortality will be evaluated by plotting Kaplan-Meier curves and compared between groups using a Cox proportional hazards model.Goodness of fit of the model will be assessed using Schoenfeld residuals to study the proportional hazard assumption and Martingale residuals to study linearity of continuous covariates.A Fine-and-Gray model will be used to compare ICU and hospital stay lengths.Cognitive status on day 28 will be compared between groups using a mixed-effects linear regression model in the population of day-28 survivors.All analyses will be adjusted on the stratification criteria.
For all analyses, P values �0.05 will be taken to indicate significant differences.The statistical analyses will be performed using SAS software v9.4 (SAS Institute, Cary, NC).
In case of missing data for the primary outcome, multiple imputation will be performed.No imputation will be performed for missing data about secondary outcomes.
Harms.Adverse events are recorded into the electronic case report form for each patient.Patients who experience one or more adverse events possibly related to ETI may be temporarily withdrawn from the trial, if deemed appropriate by the attending intensivist.

Discussion
Several recent trials have assessed the efficacy of various interventions for improving the safety of ETI in highly unstable patients [4,28,[39][40][41].Promising results have been obtained [17].Videolaryngoscopy is gaining in popularity [42,43].The intervention in our trial consists in ORI monitoring as a means of limiting desaturation during ETI.The trial thus assesses a single component of the ETI procedure, which involves many more.Whether focusing on a single component will allow the detection of a significant effect is the main issue raised by our protocol.
SpO 2 monitoring is widely used in the ICU despite the absence of randomized controlled trials demonstrating that this practice decreases mortality.We believe it would be unacceptable to abstain from using SpO 2 monitoring.Thus, all patients will have their SpO 2 values monitored using a standard pulse oximeter throughout the ETI procedure, and the results will be communicated to the intubating intensivists in both trial arms.Mean SpO 2 values obtained using standard pulse oximeters correlated well with those obtained using the Rad-97 monitor.It should be noted that relying solely on SpO 2 values for monitoring oxygenation remains controversial [44].The primary outcome (lowest SpO 2 ) is recorded from the beginning of laryngoscopy to the end of the second minute after successful intubation.This duration was chosen to avoid interactions with ventilator setting changes, in accordance with a previous study [28].Preoxygenation devices are important to the safety of intubation [45].Randomization will occur before preoxygenation.Therefore, for patients in the ORI-monitoring group whose ORI does not reach 0.6, the protocol allows a change to another preoxygenation device.
We chose an ORI cutoff of 0.6 as the preoxygenation target for several reasons.First, in an intraoperative study, 96.6% of PaO 2 values were �150 mmHg when ORI was over 0.55 [46].Second, in the NESOI1 study, 0.6 was the median ORI value at the end of preoxygenation (0.62 [0.26-0.83])[17].In the NESOI2 study, the median ORI in patients without an SpO 2 drop below 90% during intubation was close to 0.6 (0.68 [0.27-0.89]).Moreover, 0.6 is midway

Fig 5 .
Fig 5. Data collection timepoints.https://doi.org/10.1371/journal.pone.0307723.g005 Competing interests: JBL has received lecturing fees from BD and Masimo.Alexis Ferre ´reports honoraria by Fisher & Paykel for a lecture during the 2022 SFMU Congress, which bears no relation to the submitted work.None of the other authors has any competing interests to disclose.This does not alter our adherence to PLOS ONE policies on sharing data and materials.